One-week external beam partial breast irradiation: survival and toxicity outcomes.

PURPOSE: According to ASTRO and ESTRO guidelines, external beam Partial Breast Irradiation (PBI) is a valid option for early-stage breast cancer patients. Nevertheless, there is lack of consensus about the best treatment schedule. METHODS: We retrospectively analysed data of female patients treated at our institution from 2013 to 2022 with adjuvant "one-week" partial breast irradiation. Clinical Target Volume (CTV) was an isotropic expansion of 15 mm from the tumour bed (identified as the breast tissue between surgical clips). The treatment schedule was 30 Gy delivered with Volumetric Modulated Arc Therapy in 5 daily fractions. The primary endpoint was Local Control (LC). Disease-Free Survival (DFS), Overall Survival (OS) and safety were secondary endpoints. RESULTS: Three hundred and forty-four patients with a median age of 69 (33-87) years were included in the study. After a median follow-up of 34 (7-105) months, 7 patients (2.0%) developed a local recurrence. Three-year LC, DFS and OS actuarial rates were 97.5% (95% CI 96.2%-98.8%), 95.7% (95% CI 94.2%-97.2%), and 96.9% (95% CI 95.7%-98.1%), respectively. Ten (2.9%) patients experienced grade 2 late toxicities. Five (1.5%) patients reported late cardiac major events. Three (0.9%) late pulmonary toxicities were detected. One hundred and five (30.5%) patients reported fat necrosis. Good or excellent cosmetic evaluation following the Harvard Scale was reported in 252 (96.9%) cases by the physicians, while in 241 (89.2%) cases by the patients. CONCLUSION: "One-week" PBI is effective and safe, and this schedule is a valid option for highly selected early breast cancer patients.

Treatment of Advanced Merkel Cell Carcinoma: Current Therapeutic Options and Novel Immunotherapy Approaches.

Advanced Merkel cell carcinoma (MCC) is a very aggressive, rare neuroendocrine tumor of the skin with a high frequency of locoregional recurrence and metastasis, and a high mortality rate. Surgical resection, sentinel lymph node biopsy, and radiotherapy represent the gold standard of treatment in patients with localized disease, while chemotherapy has a significant role in the treatment of advanced disease. However, no definitive evidence on the survival impact of radiotherapy in the advanced stages has been provided to date, and response to chemotherapy remains brief in the majority of cases, indicating an urgent need for alternative approaches. Biological and genome sequencing studies have implicated multiple molecular pathways in MCC, thus leading to the development of new agents that target angiogenic factors, anti-apoptosis molecules, poly-ADP ribose polymerase, intracellular signal proteins such as the PI3K/AKT/mTOR pathway, and peptide receptors such as somatostatin receptors. More recently, immunotherapy agents such as avelumab, pembrolizumab, and nivolumab, which act by blocking the programmed cell-death (PD)-1/PD-L1 immune checkpoint, have shown promising results, especially in the advanced setting, and should now be considered standard of care for metastatic MCC. Current research is focusing on developing new immunotherapeutic strategies, identifying predictive biomarker to aid in the selection of patients responsive to immunotherapy, and defining combination approaches to increase efficacy in refractory patients.

Evaluation of Mediators Associated with the Inflammatory Response in Prostate Cancer Patients Undergoing Radiotherapy.

A recent "hot topic" in prostate cancer radiotherapy is the observed association between acute/late rectal toxicity and the presence of abdominal surgery before radiotherapy. The exact mechanism is unclear. Our working hypothesis was that a previous surgery may influence plasma level of inflammatory molecules and this might result in enhanced radiosensitivity. We here present results on the feasibility of monitoring the expression of inflammatory molecules during radiotherapy. Plasma levels of a panel of soluble mediators associated with the inflammatory response were measured in prostate cancer patients undergoing radical radiotherapy. We measured 3 cytokines (IL-1b, IL-6, and TNF alpha), 2 chemokines (CCL2 and CXCL8), and the long pentraxin PTX3. 20 patients were enrolled in this feasibility evaluation. All patients were treated with IMRT at 78 Gy. 3/20 patients reported grade 2 acute rectal toxicity, while 4/20 were scored as grade 2 late toxicity. CCL2 was the most interesting marker showing significant increase during and after radiotherapy. CCL2 levels at radiotherapy end could be modelled using linear regression including basal CCL2, age, surgery, hypertension, and use of anticoagulants. The 4 patients with late toxicity had CCL2 values at radiotherapy end above the median value. This trial is registered with ISRCTN64979094.

Physicists' views on hadrontherapy: a survey of members of the Italian Association of Medical Physics (AIFM).

BACKGROUND: This study was based on a survey to investigate perceptions of hadrontherapy of the members of the Italian Association of Medical Physics (AIFM). The survey was digitally submitted to the 991 members between the end of January and the beginning of April 2016. METHODS: A 19-item questionnaire was designed focusing on advantages and disadvantages of hadrontherapy, current status and possible future improvements, and need and opportunities for future investments in Italy and abroad. Information about professional qualifications, main fields of clinical involvement and specific competencies of the respondents was also collected. RESULTS: The survey was completed by 121 AIFM members (response rate 12.2%). In the answers collected, it was shown that medical physicists expressed interest in hadrontherapy mainly for reasons of personal interest rather than for professional needs (90% ± 2.5% vs. 52% ± 4.3% of the respondents, respectively), with a good knowledge of the related basic aspects as well as of the pros and cons of its application. However, poor knowledge of the current status of hadrontherapy was observed among the medical physicists not directly involved at a professional level, who were less than 3% of the physicists working in radiotherapy. CONCLUSIONS: In light of these results, the implementation of new training and education initiatives should be devised to promote a deeper and global knowledge of hadrontherapy-related issues, not only from a theoretical point of view but also in practical terms. Moreover, a close collaboration between highly specialized medical physicists employed in hadrontherapy centers and others in oncology hospitals should be -encouraged.

Eleven-year management of prostate cancer patients on active surveillance: what have we learned?

PURPOSE: To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification. METHODS: In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model. RESULTS: A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001). CONCLUSIONS: Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.

An accurate method to quantify breathing-induced prostate motion for patients implanted with electromagnetic transponders.

PURPOSE: To validate and apply a method for the quantification of breathing-induced prostate motion (BIPM) for patients treated with radiotherapy and implanted with electromagnetic transponders for prostate localization and tracking. METHODS: For the analysis of electromagnetic transponder signal, dedicated software was developed and validated with a programmable breathing simulator phantom. The software was then applied to 1,132 radiotherapy fractions of 30 patients treated in supine position, and to a further 61 fractions of 2 patients treated in prone position. RESULTS: Application of the software in phantom demonstrated reliability of the developed method in determining simulated breathing frequencies and amplitudes. For supine patients, the in vivo analysis of BIPM resulted in median (maximum) amplitudes of 0.10 mm (0.35 mm), 0.24 mm (0.66 mm), and 0.17 mm (0.61 mm) in the left-right (LR), cranio-caudal (CC), and anterior-posterior (AP) directions, respectively. Breathing frequency ranged between 7.73 and 29.43 breaths per minute. For prone patients, the ranges of the BIPM amplitudes were 0.1-0.5 mm, 0.5-1.3 mm, and 0.7-1.7 mm in the LR, CC, and AP directions, respectively. CONCLUSIONS: The developed method was able to detect the BIPM with sub-millimeter accuracy. While for patients treated in supine position the BIPM represents a reduced source of treatment uncertainty, for patients treated in prone position, it can be higher than 3 mm.

Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients.

PURPOSE: Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. METHODS: This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. RESULTS: The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. CONCLUSIONS: The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.

Urinary bladder preservation for muscle-invasive bladder cancer: a survey among radiation oncologists of Lombardy, Italy.

AIMS AND BACKGROUND: Bladder preservation is a treatment option in muscle-invasive bladder carcinoma. The most investigated approach is a trimodality schedule including maximum transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy. Our aim was to evaluate the use of bladder preservation by radiation oncologists of the Lombardy region in Italy. METHODS AND STUDY DESIGN: A survey with 13 items regarding data of 2012 was sent to all 32 radiotherapy centers within the collaboration between the Lombardy Oncological Network and the Lombardy Section of the Italian Society of Oncological Radiotherapy. RESULTS: Thirteen centers (41%) answered the survey; the presented data come from 11 active centers. In these centers, 11,748 patients were treated with external-beam radiotherapy in 2012, 100 of whom having bladder cancer (0.9%). 74/100 patients received radiotherapy as palliative treatment for T, N or M lesions. A further 9 and 5 patients received radiotherapy for oligometastatic disease (ablative doses to small volumes) and postoperatively, respectively. Bladder preservation was performed in 12 cases and included trimodality and other strategies (mainly TURBT followed by radiotherapy). A multidisciplinary urology tumor board met regularly in 5 of 11 centers. All responders declared their interest in the Lombardy multicenter collaboration on bladder preservation. CONCLUSIONS: Our survey showed that bladder preservation is rarely used in Lombardy despite the availability of the latest radiotherapy technologies and the presence of an urology tumor board in half of the centers. The initiative of multicenter and multidisciplinary collaboration was undertaken to prepare the platform for bladder preservation as a treatment option in selected patients.

The 6-year attendance of a multidisciplinary prostate cancer clinic in Italy: incidence of management changes.

UNLABELLED: Study Type - Therapy (decision analysis) Level of Evidence 2b. What's known on the subject? and What does the study add? The benefits of the multidisciplinary approach in oncology are widely recognised. In particular, managing patients with prostate cancer within a multidisciplinarity and multiprofessional context is of paramount importance, to address the complexity of a disease where patients may be offered multiple therapeutic and observational options handled by different specialists and having severe therapy-induced side-effects. The present study describes the establishing of a multidisciplinary clinic at the Prostate Cancer Programme of Milan Istituto Nazionale dei Tumori, its effects on the quality of care provided, and strategies implemented to meet upcoming needs and improve quality standards. Having analysed the data of the 2260 multidisciplinary clinics held from March 2005 to March 2011, our dynamic and modifiable organisational model was evaluated for ways to optimise the human resources, offer high-quality standards, meet new needs and ultimately reduce costs. The study is focused on the organisational aspects and adds a perspective from one of the major oncological centres of reference in Italy and in Europe. OBJECTIVES: To describe the establishing of a multidisciplinary clinic for men with prostate cancer at the Istituto Nazionale Tumori, Milan. • To evaluate the quality of care provided and to describe the management changes implemented to improve standards and meet new needs. MATERIALS AND METHODS: In March 2005, we established a multidisciplinary clinic comprising weekly clinics and case-discussion sessions. • We have altered the organisational model periodically to meet new needs and improve quality. RESULTS: We held 2260 multidisciplinary clinics up to March 2011. • For stage distribution, patients with low-risk prostate cancer increased to a peak of 61% in 2009, probably because of the anticipation of diagnosis and the active surveillance expertise of the Prostate Cancer Programme at Istituto Nazionale Tumori, Milan. The slight decrease in 2010 might be due to the availability of robot-assisted prostatectomy in several hospitals in Milan, and the start of a multicentre active surveillance protocol in December 2009. • In terms of the efficacy of our multidisciplinary strategy, 11% of drug therapies (mostly hormones) prescribed outside our institute were terminated in the multidisciplinary clinic, and 6% of indications formulated in the multidisciplinary clinics were altered during the case-discussion sessions. CONCLUSIONS: The multidisciplinary approach needs to be adaptable to meet new needs and improve quality. • Our experience has proved successful for both physicians and patients. The team agrees on strategies; complex cases are managed by a multidisciplinary team; dedicated psychologists contribute their knowledge and perspectives; and patients report the feeling of being cared for.

Salvage treatment for childhood ependymoma after surgery only: Pitfalls of omitting "at once" adjuvant treatment.

PURPOSE: To discuss the results obtained by giving adjuvant treatment for childhood ependymoma (EPD) at relapse after complete surgery only. METHODS AND MATERIALS: Between 1993 and 2002, 63 children older than 3 years old entered the first Italian Association for Pediatric Hematology and Oncology protocol for EPD (group A), and another 14 patients were referred after relapsing after more tumor excisions only (group B). Prognostic factors were homogeneously matched in the two groups. We report on the outcome of group B. RESULTS: Mean time to first local progression in group B had been 14 months. Tumors originated in the posterior fossa (PF) in 10 children and were supratentorial (ST) in 4; 11 had first been completely excised (NED) and 3 had residual disease (ED). Diagnoses were classic EPD in 9 patients, anaplastic in 5. Eight children were referred NED and 6 ED after two or more operations, 5 had cranial nerve palsy, 1 had recurrent meningitis, and 2 had persistent hydrocephalus. All received radiotherapy (RT) to tumor bed and 5 also had pre-RT chemotherapy. Six of 14 patients (6/10 with PF tumors) had a further relapse a mean 6 months after the last surgery; 4 of 6 died: progression-free survival and overall survival at 4 years after referral were 54.4% and 77%, respectively. Considering only PF tumors and setting time 0 as at the last surgery for group B, progression-free survival and overall survival were 32% and 50% for group B and 52% (p < 0.20)/70% (p < 0.29) for the 46 patients in group A with PF tumors. Local control was 32% in group B and 70.5% in group A (p = 0.02). CONCLUSIONS: Relapsers after surgery only, especially if with PF-EPD, do worse than those treated after first diagnosis; subsequent surgery for tumor relapse has severe neurologic sequelae.

External beam radiotherapy in elderly patients with clinically localized prostate adenocarcinoma: age is not a problem.

The files of 183 elderly patients aged >70 years, with localized prostate cancer (T1-3, N0-X, M0), treated with radical external radiation therapy (ERT) from January 1992 to December 2001 at the Radiotherapy Department of the Istituto Nazionale Tumori of Milan, were reviewed. Median age was 75 years. ERT represented the sole treatment for 73 patients (39.9%); in 110 cases (60.1%) hormonal therapy (HT) was associated with neoadjuvant intent. Five-year overall, disease-specific and biochemical NED (bNED) survival rates were 90.2, 93.7 and 63.2%, respectively. A subset of 23 patients aged 80 years and over were analyzed and compared to 160 men aged 70-79 years. Acute toxicity and late complications were analyzed in the two groups of patients according to the RTOG scoring system. Only 10 patients (5.4%) showed grades 2-3 (G2-3) late sequelae. The results obtained in this single-institute series highlight the pivotal role of ERT in the management of clinically localized prostate cancer in the elderly.